The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions is documented in the large number of scientific works that have appeared recently in the field of applied analgesics.
Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. Although pain is always subjective, its causes or syndromes can be classified. One of the most relevant pains is neuropathic pain which severely impairs the overall quality of life, and which is one of the most devastating forms of chronic pain.
Neuropathic pain is caused by, for example, injury of dysfunction in a peripheral or central nervous system. Disorders with neuropathic pain include, for example, disorders that exhibit hyperalgesic or allodynic symptoms, such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and persistent postoperative or posttraumatic pain.
Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.
Peripheral nerve injury or dysfunction can result in peripheral neuropathic pain. Examples are mononeuropathies (e.g., carpal tunnel syndrome, radiculopathy), plexopathies (typically caused by nerve compression, as by a neuroma, tumor, or herniated disk), and polyneuropathies (typically caused by various metabolic neuropathies. Under normal circumstances, pain sensations are carried by unmyelinated and thinly myelinated nerve fibers, designated C-fibers and A-delta fibers respectively. After a peripheral nervelesion, a neuroma may develop at the stump. The neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and elevated sensitivity to chemical, thermal and mechanical stimuli. This phenomenon is called peripheral sensitization.
Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and in some cases of stroke. In the spinal cord the spinothalamic tract (STT) constitutes the major ascending nociceptive pathway. As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons in the dorsal horn develop an increased background activity, enlarged receptive field and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization has beers proposed as an important mechanism of persistent neuropathic pairs. Non-neural glial cells and the immune response play a prominent role in central sensitization.
Typical symptoms of neuropathic pain are dysesthesias (spontaneous or evoked burning pain, often with a superimposed lancinating component), but pain may also be deep and aching. Other sensations like; hyperesthesia, hyperalgesia, allodynia (pain due to a nonnoxious stimulus), and hyperpathia (particularly unpleasant, exaggerated pain response) may also occur. Symptoms are long-lasting, typically persisting after resolution of the primary cause (if one was present) because the CNS has been sensitized and remodeled.
Peripheral nerve injury provokes a reaction in peripheral immune cells and glia at several different anatomical locations: macrophages and Schwann cells facilitate the wallerian degeneration of axotomized nerve fibers distal to a nerve lesion; an immune response in the dorsal root ganglia (DRGs) is driven by macrophages, lymphocytes and satellite cells; activation of spinal microglia dominates the early glial response in the CNS to peripheral nerve injury, which is followed by activation and proliferation of astrocytes. More recently, a specific role of the immune response and CNS-infiltrating T lymphocytes in nerve injury induced neuropathic pain development and maintenance has been identified (Cao and DeLeo, 2008; Costigan et al., 2009; Zenonos and Kim).
Migraine is a common head pain syndrome, often genetically determined, characterized by generally episodic hut often chronic, usually throbbing pain, often unilateral in distribution and often associated with photophobia, phonophobia, osmophobia, nausea and/or vomiting. The common occurrence of throbbing head pain was wrongly interpreted earlier for the pain to arise from blood vessels; but current research points to a neural origin of the migraine pain. Several observations made over the past two decades raised the issue that there is likely to be a central pain mechanism in migraine (Afridi and Goadsby, 2003; Goadsby, 2002).
Current therapy for neuropathic pain aims only at reducing symptoms, generally by suppressing neuronal activity. Thus treatment options, e.g. NSAIDS, antidepressants, anticonvulsants, baclofen, neuromodulation modalities or opiates, predominantly alleviate symptoms via nonspecific reduction of neuronal hyperexcitability rather than targeting the specific etiologies.
Therefore, effective and improved methods and compounds that we able to treat neuropathic pain are needed.